A major route of levodopa and dopamine metabolism is by O-methylation catalyzed by catechol-O-methyl transferase (COMT). We will study the in vivo effect of a COMT inhibitor, U-0521, that had been used safely in humans. Initial studies in rats will evaluate the pharmacologic properties of this drug in the presence of high dosage levodopa administration, with and without concomitant carbidopa (a peripheral dopa decarboxylase inhibitor), similar to the treatment of parkinsonism. Time course, dose-response curves, toxicity and behavioral evaluations, and effects of chronic treatment will be studied. We will also evaluate the pharmacokinetics of levodopa administration in rats and in patients treated for parkinsonism, with emphasis on the role of the newly discovered high concentrations of levodopa present in erythrocytes. It is possible that levodopa in erythrocytes, in addition to that in serum, may serve as a source of levodopa for brain. The hypothesis is proposed that levodopa in erythrocytes may play an important role as a bioavailable source of levodopa for brain. This hypothesis will be evaluated in patients, particularly in relationship to the frequent problem of the "on-off" effect encountered in long-term treatment with levodopa. The kinetics of uptake, storage, and metabolism of levodopa in human and rat erythrocytes will be studied. We will evaluate the possibility that U-0521, by inhibiting methylation of levodopa in erythrocytes, prolongs the storage of high concentrations of levodopa in these cells, which might ultimately prove useful in the therapy of parkinsonism. After the basic studies are carried out in rats, we will attempt to conduct Phase I testing of U-0521 in patients with parkinsonism. The ultimate goal is to determine if a COMT inhibitor will enhance the therapeutic effects of levodopa therapy in parkinsonism and prevent some of the intolerable adverse effects encountered in present-day therapy.